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For most manufacturing and packaging processes it is technically not feasible or much too expensive to check every single unit of resulting product (100% control). Instead, random samples are relied on which are taken on an ongoing basis at specific times during the process (in-process controls), or random samples are taken for quality control of the final product prior to market release.

對(duì)于大多數(shù)生產(chǎn)和包裝工藝，檢查每一個(gè)產(chǎn)品(100%檢測(cè))在技術(shù)上不可行或太昂貴。相反，隨機(jī)抽樣依賴于在持續(xù)進(jìn)行的工藝中特定時(shí)間的抽樣(中間控制)，或者隨機(jī)抽樣用于在上市放行之前對(duì)最終產(chǎn)品進(jìn)行質(zhì)量控制。

 

However, it would hardly be possible to find the famous needle in the haystack using these random samples. For this reason,validated manufacturing and packaging processes are required by law in addition to the final product checks and IPCs. The company must prove that the processes are all so reliable that, under everyday routine manufacturing conditions, they result in medicinal products of a high and reproducible quality.

然而，使用這些隨機(jī)樣本幾乎不可能在大海撈針中找到顯著的針。因此，除了最終產(chǎn)品檢查和IPC之外，法律還要求驗(yàn)證生產(chǎn)和包裝工藝。公司必須證明所有的工藝都是可靠的，在日常的常規(guī)生產(chǎn)條件下，它們能生產(chǎn)出高質(zhì)量和可重復(fù)的藥品。

 

Process validation 工藝驗(yàn)證

 

Process validation is time-consuming and has to be carried out on every single product before the marketing authorisation is granted. It must be carried out after the development of the manufacturing and packaging process has been completed and the process has been adapted to the manufacturing environment (optimised).

工藝驗(yàn)證是耗時(shí)的，必須在批準(zhǔn)上市許可之前對(duì)每個(gè)產(chǎn)品進(jìn)行驗(yàn)證。它必須在生產(chǎn)和包裝工藝的開發(fā)完成后進(jìn)行，并且該工藝已適應(yīng)生產(chǎn)環(huán)境(經(jīng)過優(yōu)化的)。

 

The planning and implementation of process validation can vary greatly depending on the company and products. For this reason, every pharmaceutical manufacturer must describe in avalidation master plan (VMP) how validations are organised in practise, e.g. who belongs to the validation team, who creates, checks and approves the validation documents, and who is responsible for making what decisions.

工藝驗(yàn)證的計(jì)劃和實(shí)施可能因公司和產(chǎn)品的不同而有很大差異。因此，每個(gè)制藥商必須在驗(yàn)證主計(jì)劃(VMP)中描述驗(yàn)證在實(shí)踐中是如何組織的，例如，誰(shuí)屬于驗(yàn)證團(tuán)隊(duì)、誰(shuí)創(chuàng)建、檢查和批準(zhǔn)驗(yàn)證文件，以及誰(shuí)負(fù)責(zé)做出哪些決定。

 

Avalidation plan must be created for each individual product, describing the validation program for the respective product in detail. The effort required depends largely on the type of product.

必須為每個(gè)單獨(dú)的產(chǎn)品創(chuàng)建驗(yàn)證計(jì)劃，詳細(xì)描述各個(gè)產(chǎn)品的驗(yàn)證程序。所需的努力在很大程度上取決于產(chǎn)品的類型。

 

Is the manufacturing or packaging process straightforward or complex?

生產(chǎn)或包裝過程是簡(jiǎn)單的還是復(fù)雜的?

 

Does it require special equipment and specially trained personnel?

是否需要特殊的設(shè)備和受過特殊訓(xùn)練的人員?

 

Is the product risk particularly high, e.g. because the product is very sensitive or because it must be sterile?

產(chǎn)品風(fēng)險(xiǎn)是否特別高，例如，因?yàn)楫a(chǎn)品非常敏感或必須無菌?

 

How much experience does the company have with similar processes and products?

公司在類似工藝和產(chǎn)品方面有多少經(jīng)驗(yàn)?

 

Are reliable control mechanisms in place that detect quality issues before the product leaves the company?

是否有可靠的控制機(jī)制在產(chǎn)品出廠前檢測(cè)出質(zhì)量問題?

 

The validation team evaluates these sorts of questions usingquality risk analyses.

驗(yàn)證團(tuán)隊(duì)使用質(zhì)量風(fēng)險(xiǎn)分析來評(píng)估這類問題。

 

Depending on the results of the risk evaluation, the team decides on the extend of validation studies needed. For example:

根據(jù)風(fēng)險(xiǎn)評(píng)估的結(jié)果，團(tuán)隊(duì)決定所需驗(yàn)證研究的范圍。例如:

 

How many batches have to be produced as validation batches?

需要生產(chǎn)多少批次作為驗(yàn)證批次?

 

What other tests have to be carried out?

還需要進(jìn)行哪些測(cè)試?

 

What results need to be achieved to ensure that the process is absolutely reliable (acceptance criteria)?

需要達(dá)到什么結(jié)果來確保工藝是絕對(duì)可靠的(可接受標(biāo)準(zhǔn))?

 

Everything must be described in detail in thevalidation plan and test plans and approved before manufacture of the validation batches begins.

每件事都必須在驗(yàn)證計(jì)劃和測(cè)試計(jì)劃中詳細(xì)描述，并在驗(yàn)證批次開始生產(chǎn)之前得到批準(zhǔn)。

 

The tests that are specified in the plans, and any observations or difficulties are documented invalidation records during manufacture.

計(jì)劃中規(guī)定的測(cè)試以及任何觀察結(jié)果或困難都記錄在生產(chǎn)過程中的驗(yàn)證記錄中。

 

Thevalidation report summarises the results for all validation batches and states if the manufacturing and packaging processes are reliable. The validation of the process is only complete when the validation report has been approved. The manufactured medicinal product may not be released for sale beforehand!

驗(yàn)證報(bào)告總結(jié)了所有驗(yàn)證批次的結(jié)果，并說明生產(chǎn)和包裝工藝是否可靠。只有當(dāng)驗(yàn)證報(bào)告被批準(zhǔn)時(shí)，工藝的驗(yàn)證才算完成。生產(chǎn)的藥品不得提前放行銷售!（相關(guān)文章見：483表格：通過臨時(shí)變更來放行未完成檢測(cè)的API是不合規(guī)的）

 

Validation shows that under routine conditions a process always results in high-quality products.

驗(yàn)證表明，在常規(guī)條件下，工藝總是生產(chǎn)出高質(zhì)量的產(chǎn)品。

 

Process optimisation and process changes

工藝優(yōu)化和工藝變更

 

A successful validation is only valid as long as the process and all of the conditions (e.g. facilities, specifications, starting materials, suppliers) remain within the specified ranges that were checked during validation. For this reason, manufacturing, packaging, cleaning and operating instructions must always be followed meticulously during routine production. If this is not possible in a particular case, the employees must record what was done instead in thebatch record or deviation reports.

只有當(dāng)工藝和所有條件(如設(shè)施、標(biāo)準(zhǔn)、起始物料、供應(yīng)商)保持在驗(yàn)證期間檢查的規(guī)定范圍內(nèi)時(shí)，成功的驗(yàn)證才有效。因此，在日常生產(chǎn)中，必須嚴(yán)格遵守制造、包裝、清潔和操作說明。如果在特定情況下不能這樣做，員工必須在批記錄或偏差報(bào)告中記錄所做的工作。

 

Changes to or improvements of validated processes, e.g. an increase in the process temperature or improvement of the formulation, must only be carried out after they have been examined thoroughly and approval is given (change control). Some changes, even require complete or partial repetition of the validation (revalidation). For certain changes a change request must be submitted to the authorisation authorities.

變更或改進(jìn)已驗(yàn)證的工藝，例如提高工藝溫度或改進(jìn)配方，必須在經(jīng)過徹底檢查并獲得批準(zhǔn)后才能進(jìn)行(變更控制)。有些變更甚至需要完全或部分重復(fù)驗(yàn)證(重新驗(yàn)證)。對(duì)于某些變更，必須向監(jiān)管機(jī)構(gòu)提交變更請(qǐng)求。